# Pathogenic Neurofibromatosis type 1 gene variants in tumors of non‐NF1 patients and role of R1276

## TL;DR

The paper explores pathogenic NF1 gene variants in tumors of patients without NF1, highlighting their frequency and impact on cancer development.

## Contribution

The study identifies emerging somatic NF1 variants and emphasizes the role of R1276 in cancer-related neurofibromin dysfunction.

## Key findings

- Pathogenic NF1 variants were found in 32% of sequenced patients, most commonly in lung cancer, glioma, and melanoma.
- Recurrent variants at R1276 suggest a key role in neurofibromin dysfunction in cancer.
- Somatic NF1 mosaicism is more common than previously assumed and requires multitissue sampling for accurate detection.

## Abstract

Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome associated with pathogenic variants affecting the GTPase‐activating protein neurofibromin. Genetic variants affect neurofibromin through targeted protein degradation, failed aggregation of the monomers or failure of specific domains depending on the functional state. In addition to the occurrence in NF1, there is evidence of pathogenic variants occurring in various solid tumors. We collected data from 63 patients from our molecular tumor board for NF1 gene sequencing and detected 72 NF1 variants, thereby 32% of those being pathogenic. They occurred most often in lung cancer, glioma, melanoma, sarcoma, and gynecological cancer and affected women more often. Pathogenic NF1 variants appeared at low frequency except in malignant melanoma and glioma (10%). We present common pathogenic variants, their types, and association with tumor entities, their frequency, and domain localization and focus on common recurrent variants and their probable result and predictive quality in somatic mutation screening. We detected variants in different tumor entities without NF disease, covering more frequent truncating mutations than reported for germline. We question whether all NF1 variants reported in tumors without the presence of NF1 are somatic. To conclude, recognition of NF1 mosaicism requires multitissue sampling, precise sequencing technologies, and inclusion of genetic counseling.

Somatic variants of the neurofibromatosis type 1 (NF1) gene occur across neoplasms without clinical manifestation of the disease NF1. We identified emerging somatic pathogenic NF1 variants and hotspots, for example, at the arginine finger 1276. Those missense variants provide fundamental information about neurofibromin's role in cancer. Somatic NF1 mosaicism is more common than assumed, demanding greater attention in tumor boards.